The present invention is directed to alicyclic imidazoles which interact with the histamine H3 receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H3 receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer""s, schizophrenia, obesity and migraines.
Histamine plays a role in regulating attentiveness and cognition in the central nervous system (CNS), and histamine levels in the brain are controlled by the histamine H3 receptor. Moreover, serotonin, norepinephrine, dopamine and acetylcholine all have been demonstrated to be regulated by the histamine H3 receptor. These neurotransmitters are known to play a role in many CNS psychiatric disorders involving higher cognitive function and/or emotion, Consequently, compounds affecting H3 receptor function (as agonists, antagonists or inverse agonists) could have utility in the treatment of a variety of CNS maladies, including but not limited to dementias, attention deficit hyperactivity disorder, depression, anxiety and schizophrenia.
Histamine is also involved in the control of sleep/wake states and appetite. Accordingly, histamine H3 receptor ligands might be expected to be useful in treating insomnia, narcolepsy, age-related sleep disorders, obesity and anorexia. Although they exist in low density outside of the brain, histamine H3 receptors are found on the sympathetic and parasympathetic nerve terminals in the periphery, including the vasculature and heart. Thus, compounds that alter histamine H3 receptor activity might also have clinical utility in treating conditions such as migraine and cardiac dysfunction.
Various imidazole-containing compounds are disclosed in WO 92/15567, WO 93/12107, and U.S. Pat. Nos. 5,217,986 and 5,559,113. 2-(4-imidazolyl)cyclopropylamine is disclosed in U.S. Pat. No. 4,767,778. 1H-4(5)-substituted imidazole derivatives are disclosed in WO 96/38142 and U.S. Pat. No. 6,072,057. 2-(1H-4(5)-imidazoyl)cyclopropyl derivatives are disclosed in U.S. Pat. Nos. 6,008,240; 5,990,317 and 5,652,258. However, there is still a need for novel, histamine H, receptor-active imidazoyl cyclopropyl derivatives.
The present invention is directed to alicyclic imidazoles which interact with the histamine H3 receptor as agonists, antagonists or inverse agonists; pharmaceutically active compositions containing such compounds; and the use of such compounds in formulations for the control or prevention of disease states in which histamine H3 receptors are involved, such as allergy, inflammation, hypotension, glaucoma, sleeping disorders, states of hyper- and hypo-motility of the gastro-intestinal tract, cardiovascular disease, hypo- and hyper-activity of the central nervous system, Alzheimer""s, schizophrenia, obesity and migraines.
The invention is directed to novel compounds of Formula I as follows: 
wherein n is an integer of zero to six;
p is an integer of zero to two;
q is an integer of zero to four;
T is selected from the group consisting of xe2x80x94NR6R7, xe2x80x94N(R8)C(NR9)R10, xe2x80x94CN, xe2x80x94OH, xe2x80x94H, xe2x80x94OR11, xe2x80x94OC(O)R12, xe2x80x94C(O)R13, xe2x80x94C(O)NH2, xe2x80x94C(Nxe2x80x94OH)H, xe2x80x94SC(S)R14, xe2x80x94NR15C(S)R16, xe2x80x94NR17C(O)R18, xe2x80x94SC(NR19)R20, xe2x80x94OC(NR21)R22, R23, xe2x80x94N(R24)C(O)N(R25), xe2x80x94N(R26)C(O), and xe2x80x94O(O)NR27R28;
R1 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, xe2x80x94C(O)N(C1xe2x80x94C3 alkyl)2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and xe2x80x94C(O)NH(benzyl); and
R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 and R28 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94NO2, amino, xe2x80x94CN, carboxy, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and xe2x80x94C(O)NH(benzyl);
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 and R28 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and pharmaceutically acceptable salts thereof;
with the proviso that when T is xe2x80x94NR6R7, R1 is hydrogen and n is zero, R6 and R7 are not both hydrogen;
and the proviso that when T is xe2x80x94OH, n is one, R4 and R5 are each hydrogen, and p and q are zero, R1 is not triphenylmethyl;
and the proviso that when T is xe2x80x94C(O)R13 and n is zero, R13 is not hydrogen or a chiral moiety.
For compounds of Formula I, n may be an integer of zero to three; R1 may be hydrogen, R2, R3, R4 and R5 may each independently be hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl or aryl; and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 may each be hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl. Presently preferred compounds of Formula I have T as xe2x80x94N(R8)C(NR9)R10, xe2x80x94OC(O)R12, xe2x80x94C(O)R13, xe2x80x94C(O)NH2, xe2x80x94C(Nxe2x80x94OH)H, xe2x80x94SC(S)R14, xe2x80x94NR15C(S)R16, xe2x80x94NR17C(O)R18, xe2x80x94SC(NR19)R20 or xe2x80x94OC(NR21)R22 when n is zero or T as xe2x80x94NR6R7, xe2x80x94CN, xe2x80x94OH, xe2x80x94H, xe2x80x94OR11 or R23 when n is one.
More specifically, the compounds of this invention may be described by Formula II below 
wherein n is an integer of zero to three;
T is selected from the group consisting of xe2x80x94NR6R7, xe2x80x94N(R8)C(NR9)R10, xe2x80x94CN, xe2x80x94OH, xe2x80x94H, xe2x80x94OR11, xe2x80x94OC(O)R12, xe2x80x94C(O)R13, xe2x80x94C(O)NH2, xe2x80x94C(Nxe2x80x94OH)H, xe2x80x94SC(S)R14, xe2x80x94NR15C(S)R16, xe2x80x94NR17C(O)R18, xe2x80x94SC(NR19)R20, xe2x80x94OC(NR21)R22 and R23;
R1 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94N(C1-C3 alkyl)xe2x80x94C(O)(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and xe2x80x94C(O)NH(benzyl); and
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, xe2x80x94CF3, xe2x80x94NO2, amino, xe2x80x94CN, carboxy, xe2x80x94N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94NHC(O)NH(C1-C3 alkyl), xe2x80x94NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, xe2x80x94SO2xe2x80x94(C1-C3 alkyl), xe2x80x94SO3xe2x80x94(C1-C3 alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and xe2x80x94C(O)NH(benzyl);
wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof;
with the proviso that when T is xe2x80x94NR6R7, R1 is hydrogen and n is zero, R6 and R7 are not both hydrogen;
and the proviso that when T is xe2x80x94OH, n is one, and R4 and R5 are each hydrogen, R1 is not triphenylmethyl;
and the proviso that when T is xe2x80x94C(O)R13 and n is zero, R13 is not hydrogen or a chiral moiety.
For presently preferred compounds of Formula II, R1 may be hydrogen; R3 may be hydrogen or lower alkyl; R4 and R5 may each be hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl or aryl; and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 may each be hydrogen, lower alkyl, alkenyl, alkynyl, aryl or heterocyclyl. Presently preferred compounds of Formula II have T as xe2x80x94N(R8)C(NR9)R10, xe2x80x94OC(O)R12, xe2x80x94C(O)R13, xe2x80x94C(O)NH2, xe2x80x94C(Nxe2x80x94OH)H, xe2x80x94SC(S)R14, xe2x80x94NR15C(S)R16, xe2x80x94NR17C(O)R18, xe2x80x94SC(NR19)R20 or xe2x80x94OC(NR21)R22 when n is zero or T as xe2x80x94NR6R7, xe2x80x94CN, xe2x80x94OH, xe2x80x94H, xe2x80x94OR11 or R23 when n is one.
More specifically, the compounds of this invention may be described by Formula III below 
wherein T is selected from the group consisting of xe2x80x94N(R8)C(NR9)R10, xe2x80x94OC(O)R12, xe2x80x94C(O)R13, xe2x80x94C(O)NH2, xe2x80x94C(Nxe2x80x94OH)H, xe2x80x94SC(S)R14, xe2x80x94NR15C(S)R16, xe2x80x94NR17C(O)R18, xe2x80x94SC(NR19)R20 and xe2x80x94OC(NR21)R22;
R3 is selected from the group consisting of hydrogen and lower alkyl; and,
R8, R9, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl;
wherein R3, R8, R9, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof;
with the proviso that when T is xe2x80x94C(O)R13, R13 is not hydrogen or a chiral moiety.
More specifically, the compounds of this invention may be described by Formula IV below 
wherein T is selected from the group consisting of xe2x80x94NR6R7, xe2x80x94CN, xe2x80x94OH, xe2x80x94H, xe2x80x94OR11 and R23;
R3 is selected from the group consisting of hydrogen and methyl;
R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, alkenyl, alkynyl and aryl; and,
R6, R7, R11 and R23 are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aryl and heterocyclyl;
wherein R3, R4, R5, R6, R7, R11 and R23 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof.
Formulae I-IV also encompass esters, carbamates, aminals, amides, optical isomers or pro-drugs thereof.
Presently preferred compounds include 4-(trans-2-cyano-cyclopropyl)imidazole, 4-(trans-2-aminocarbonyl-cyclopropyl)imidazole, 4-(trans-2-amidino-cyclopropyl)imidazole, 4-(trans-2-aminomethyl-cyclopropyl)imidazole, 4-(trans-2-N-hydroxyimino-cyclopropyl)imidazole, 4-(trans-2-hydroxymethyl-cyclopropyl)imidazole, 4-(trans-2-N-methylamidino-cyclopropyl)imidazole, 4-(trans-2-aminomethyl-2-methyl-cyclopropyl)imidazole, 4-(trans-2-amidino-2-methyl-cyclopropyl)imidazole and pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention; and a method for regulation of histamine H3 receptors in a mammal by agonism, antagonism, or inverse agonism of said receptors, comprising administering to a mammal in need of such regulation a therapeutic amount of a compound of the present invention.